DESCRIPTION: Mouse mammary tumor virus (MMTV) is a type B retrovirus that is transmitted through milk and causes mammary carcinomas in mice. The ultimate target tissue for MMTV is the mammary gland, where viral integration near cellular oncogenes results in mammary tumors. However, MMTV also utilizes the cells of the immune system in its journey from milk to the mammary gland of offspring that suckle on viremic mothers. A better understanding of how MMTV infects these different cell types and reaches its target tissue is dependent on identifying the cell surface receptor(s) that the virus uses to infect cells. Preliminary data are presented indicating that the applicant recently cloned the MMTV receptor (MTVR). The goal of the experiments described in this proposal is to characterize this cell surface receptor and to study its role in MMTV transmission and mammary gland infection. Detailed analysis of the gene structure, transcripts and of the encoded protein will allow the applicant to understand why MMTV only infects and transforms specific cell types. Moreover, the role of the receptor in virus transfer between different cell types will be studied. Targeted mutation of the receptor genes in tissue culture cells and in transgenic animals will be performed, to test if the gene is necessary and sufficient for MMTV infection of all cell types and to begin to determine its normal cellular function. The human equivalent of the MTVR gene will be cloned and used in "domain swap" experiments to determine what sequences within the mouse MTVR are required for virus binding.